Drug-eluting stents (DES) are deployed to physically reopen stenotic regions of coronary arteries to restore blood flow to the heart and to inhibit restenosis by release of anti-proliferative drugs over an extended period. However, significant incidences of localized delayed inflammation and late stent thrombosis (LST) leading to morbidities and deaths several months-to-years after deployment were reported in 2006. These alerted the FDA to reconsider the safety of DES and to issue a safety warning. Because DES inhibits restenosis, the stent struts remain at the arterial surface in indefinite contact with the flowing blood instead of being rapidly overgrown by the neointima. Although averaging only 1005m in height, the struts significantly change the local flow characteristics to create flow separation zones containing unsteady vortices in the regions adjacent to the stent strut. These vortices are characterized by significantly lower blood flow velocities than the bulk flow and prolonged particle residence time. We propose that the flow separation regions represent micro-reaction chambers where pro-coagulant and pro-inflammatory elements from the blood and vessel wall accumulate. Furthermore, re-endothelialization of the stented region is inhibited by low shear stress of the separation zones thereby contributing to a pro-pathological environment. Learning from numerical simulations of coronary blood flow and our extensive hemodynamic studies of arterial geometries where natural blood flow disturbances such as unsteady vortices induce pro-pathological vascular cell phenotypes, we hypothesize that the stent strut geometry leads to a local pro-thrombotic and pro-inflammatory environment. This R21 research grant proposes topographic solutions to mitigate or eliminate these consequences and tests them by experiment under controlled conditions in vitro, which is a necessary set of proof-of-principle exploratory studies that precede experiments in vivo. Guided by fundamental fluid dynamic principles, CFD numerical simulations identified a range of streamlined stent strut geometries that minimize or eliminate flow separation. Aim 1 will use Particle Image Velocimetry to characterize the flow field about different manufactured strut stent geometries in a cell culture flow chamber modeling coronary arterial flow and in a flow tube scaled to manageable quantities of whole blood. Aim 2 will test the effects of the respective strut designs on deposition of activated platelets and characteristics of thrombus growth in a chemical and substrate milieu conducive to thrombosis. Finally, Aim 3 will evaluate the effects of the redesigned stents on re-endothelialization and the expression of coagulation-related molecular phenotypes of endothelium. The proposal addresses the mechanisms of an important clinical problem by exploring the potential high utility of stent redesign and is built upon our extensive experience in hemodynamics, biomedical engineering and vascular cell and molecular pathology. The same principles of streamlined strut design are also applicable to BMS where thrombosis linked to the physical presence of the stent at the vessel surface occurs earlier, before a neointima develops. PUBLIC HEALTH RELEVANCE: Coronary artery stents are a common and effective treatment for angina and heart attacks particularly when the metal stent is coated with a slow-release drug that inhibits tissue response-driven reclosure (restenosis) of the artery (drug eluting stents;DES). Recently however, late stent thrombosis has been reported in a significant number of DES patients after anti-coagulant therapy has ended months after stent deployment. This project proposes that the physical shape of currently used stent struts creates a flow environment that promotes inflammation and thrombosis, and that a streamlined stent strut geometry will reduce or eliminate flow disturbances with a predicted decrease in thrombosis risk. Before taking the streamlined designs into an animal model, it is important to optimize the geometry by conducting numerical simulations and proving it with experimental fluid flow measurements while demonstrating proof of biological principles through controlled experiments using blood and vascular cells. The project tests an important hemodynamics hypothesis related to stent function and is an essential exploratory bridge to preclinical testing in an animal model. Successful implementation of effective stent redesign will have an important impact on the use and efficacy of stents.